Process for preparing intermediates for the manufacture of discodermolide and discodermolide analogues

ABSTRACT

The invention relates to a process for the preparation of a substituted alkene of formula (I) wherein R 1 , R 2  and R 3  are independently of each other a protecting group for a hydroxy group or hydrogen and R 4  is phenyl which is unsubstituted or mono- or disubstituted by alkoxy, which alkene constitutes an intermediate for the preparation of discodermolide and discodermolide analogues.

The invention relates to a process for preparing intermediates for themanufacture of discodermolide and discodermolide analogues and to theintermediates obtained during the process.

(+)-Discodermolide is a polyketide natural product that was isolatedfrom extracts of the marine sponge Discodermolide dissoluta byresearchers at the Harbor Branch Oceano-graphic Institution [S. PGunasekera et al., J. Org. Chem. 1990;55:4912-15 (published erratumappears in J. Org. Chem. 1991;56:1346)]. Discodermolide lacks obviousstructural resemblance to paclitaxel, yet it shares with paclitaxel (theactive substance in the drug Taxol®) the ability to stabilizemicrotubules. Paclitaxel has proven to be useful in treating some typesof cancer in clinical practice. Discodermolide binds to tubulincompetitively with paclitaxel and was shown to have utility againsthyperproliferative disorders (see, e.g., WO 97/20835). Futuredevelopment of discodermolide or structurally related analogues ishindered by the lack of a natural source that could provide greateramounts of the compound, since naturally occurring discodermolide isscarce and harvesting the producing organism presents logisticalproblems. Also lacking is a feasible synthetic route. Accordingly, thereis a need for improved processes of manufacture of discodermolide andanalogues thereof and for novel intermediates for such processes ofmanufacture which processes and intermediates enable the manufacture ofcommercially acceptable quantities of discodermolide and structurallyrelated analogues.

The present invention relates to a process for preparing a substitutedalkene of formula I

wherein R₁, R₂ and R₃ are independently of each other a protecting groupfor a hydroxy group or hydrogen and R₄ is phenyl which is unsubstitutedor mono- or disubstituted by alkoxy, in which process a sulfonate offormula (II)

wherein R₁, R₂ and R₃ are all protecting groups for a hydroxy groupwhich protecting groups can be identical or different, R₄ has themeaning as defined for the compound of formula I and R₅ is alkyl or arylwhich is unsubstituted or substituted by alkyl, is reduced, e.g., bytreatment with NaBH₄, LIBH₄, diisobutyl aluminium hydride, LiB(ethyl)₃H,Zn, tributyl tin hydride or, preferably, LiAlH₄, and afterwards, ifdesired, one, two or all protecting groups R₁, R₂ and R₃, in particularthe protecting group R₁, are detached. Suitable reaction conditions fora reduction utilising LiAlH₄ are, for example, described in J. Org.Chem. 1980, 45, 2550 to 2551 or also J. Am. Chem. Soc. 1951, 73, on page2874 (second Example described there). NaBH₄ can, for example, generallybe employed in dimethyl sulfoxide or sulfolane at a temperature between15° C. and 100° C., e.g. 25° C. or 85° C., and tributyl tin hydridegenerally in refluxing 1,2-dimethoxyethane (DME) in the presence ofsodium iodid.

Furthermore, the present invention relates to a process for preparing asubstituted alkene of formula I wherein R₁, R₂ and R₃ are independentlyof each other a protecting group for a hydroxy group or hydrogen and R₄is phenyl which is unsubstituted or mono- or disubstituted by alkoxy, inwhich process the carboxylic ester of the formula III

wherein R₁, R₂ and R₃ are all protecting groups for a hydroxy groupwhich protecting groups can be identical or different, R₆ is alkyl orarylalkyl, and R₄ has the meaning as defined for the compound of formulaI, is first reduced, e.g., by treatment with LiAlH₄, the obtainedalcohol of the formula IV

wherein R₁, R₂, R₃ and R₄ have the meanings as defined above for thecompound of formula III, which is further reacted with a compound offormula VR₅SO₂Hal  (V)wherein R₅ is alkyl or aryl which is unsubstituted or substituted byalkyl, and Hal represent halogen under reaction conditions known as suchand the obtained sulfonate of formula IIwherein R₁, R₂, R₃ and R₄ have the meanings as defined for thecarboxylic ester of formula III and R₅ is alkyl or aryl which isunsubstituted or substituted by alkyl, is further reduced, e.g., bytreatment with LiAlH₄, and, if desired, one, two or all protectinggroups R₁, R₂ and R₃ are detached by methods known in the art.

Additionally, the present invention relates to a process for preparing acarboxylic ester of formula III wherein R₁ and R₂ are protecting groupsfor a hydroxy group which protecting groups can be identical ordifferent, R₃ is hydrogen, R₄ is phenyl which is unsubstituted or mono-or disubstituted by alkoxy, and R₆ is alkyl or arylalkyl, In whichprocess an allyl halide of the formula VI

wherein R₁ and R₂ have the meanings as defined for a carboxylic ester offormula III and X is halogen, preferably bromine or iodine, is reactedwith a carboxylic ester of formula VII

wherein R₃, R₄ and R₆ have the meanings as defined for a carboxylicester of formula III in the presence of a base.

The invention also especially relates to a sulfonate of formula IIwherein R₁, R₂ and R₃ are all protecting groups for a hydroxy groupwhich protecting groups can be identical or different, R₄ is phenylwhich is unsubstituted or mono-or disubstituted by alkoxy, preferablymonosubstituted by alkoxy, and R₅ is alkyl or aryl which isunsubstituted or substituted by alkyl and to the synthesis of suchsulfonate. Preferably in such sulfonate of formula II, R₁ and R₂ areidentical, R₁, R₂ and R₃ are benzyl or silyl protecting groups, and R₅is lower alkyl or phenyl which is substituted, most preferablymonosubstituted, by lower alkyl. In a very preferred embodiment, R₁ andR₂ and R₃ are all tert-butyl dimethylsylyl, R₄ is phenyl which isunsubstituted or monosubstituted by methoxy and R₅ is methyl or phenylwhich is monosubstituted by lower alkyl.

Furthermore, the invention especially relates to a carboxylic ester offormula III wherein R₁ and R₂ are protecting groups for a hydroxy groupwhich protecting groups can be identical or different, R₃ is aprotecting group for a hydroxy group or hydrogen, R₄ is phenyl which isunsubstituted or mono- or disubstituted by alkoxy, and R₆ is alkyl orarylalkyl. In a preferred embodiment of the invention, the carboxylicester of formula III comprises radicals R₁ and R₂, which are identical,R₁, R₂ and R₃ are silyl protecting groups and R₆ is lower alkyl.

Furthermore, the invention especially relates to an alcohol of formulaIV wherein R₁, R₂ and R₃ are all protecting groups for a hydroxy groupwhich protecting groups can be identical or different and R₄ is phenylwhich is unsubstituted or mono- or disubstituted by alkoxy.

Additionally, the present invention relates to a carboxylic ester offormula VII wherein R₃ is hydrogen, R₄ is phenyl which is unsubstitutedor mono- or disubstituted by alkoxy, and R₆ is alkyl or arylalkyl.

Furthermore, the invention relates to an oxazolidinone of formula VIII

wherein Ph denotes phenyl, and R₁ and R₂ are independently of each othera silyl protecting group, hydrogen or benzyl which is unsubstituted ormono- or disubstituted by lower alkoxy, or R₁ and R₂ together representmethyliden substituted by phenyl which phenyl group is mono- ordisubstituted by lower alkoxy, and to an oxazolidinone of formula IX

wherein Ph denotes phenyl and R₁ and R₂ are independently of each othera silyl protecting group, hydrogen or benzyl which is unsubstituted ormono- or disubstituted by lower alkoxy under the proviso that one ofboth radicals R₁ and R₂ is a silyl protecting group.

Moreover, the invention relates to a δ-valerolactol of the formula X

wherein R₂ is a protecting group for a hydroxy group and to an alcoholof the formula XI

wherein both R₁ and R₂ represent a silyl protecting group.

Additionally, the invention relates to the use of a sulfonate of formulaII, of a carboxylic ester of formula II, an alcohol of formula IV or acarboxylic acid of formula VII, all as defined above, in a process forthe manufacture of (+)-discodermolide or discodermolide analogues.

Furthermore, the invention relates to a process for preparing an etherof formula XXVI

wherein R₁ is benzyl which is mono- or disubstituted by alkoxy, R₂represents a protecting group for a hydroxy group or hydrogen and R₁₀ isN-oxazolidinyl which is unsubstituted or substituted by alkyl, benzyl orphenyl; OR_(e) wherein R_(e) is alkyl or benzyl, or N(R_(a))₂ whereinR_(a) is alkyl or benzyl, in which process a compound of formula XXVII,

in which the radicals R₂ and R₁₀ are as defined for the compound offormula XXVI, is reacted with a trichloroacetimidate of formula XVII,

wherein m is 1 or 2 and alkoxy is preferably lower alkoxy, in particularmethoxy, in the presence of catalytic amounts of samarium triflate orytterbium triflate in a suitable solvent, especially dichloromethane, ata temperature between −15° C. and +15° C., preferably between −5° C. and+5° C., in particular at about 0° C., and afterwards, if desired, theprotecting group R₂ is split off.

Within the present disclosure, the general definitions used hereinbeforeand hereinafter preferably have the following meaning, if not indicatedotherwise:

The prefix “lower” means that the respective moiety preferably has up toand including a maximum of 7 carbon atoms, more preferably up to 4carbon atoms.

A protecting group for a hydroxy group as defined herein is a protectinggroup that can be detached under basic or neutral conditions, i.e. in amedium having a pH≧7, and is especially benzyl which is unsubstituted ormono-or disubstituted by alkoxy, in particular lower alkoxy, preferablymethoxy, or, more particular, a silyl protecting group. A silylprotecting group is a group consisting of a silicium atom having a freevalence and bearing three groups selected from aryl, alkyl andarylalkyl. A silyl protecting group is in particular a trialkylsilyl- ordiaryl-alkylsilyl protecting group, like triethylsilyl, diethylisopropylsilyl, and, very preferably, tert-butyl dimethylsilyl.

Alkyl is preferably lower alkyl which can be linear or branched and isespecially ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or,preferably, methyl or tert-butyl.

Alkoxy is preferably lower alkoxy, e.g. ethoxy or tert-butoxy, and verypreferably methoxy.

Aryl is in particular C₆-C₁₀aryl, especially phenyl or naphthyl.

Arylalkyl is in particular benzyl.

Halogen is preferably fluorine, chlorine, bromine or iodine.

Any reference to other documents or publications within this applicationmeans that the respective document or publication is included byreference into the present disclosure.

Substituted alkenes of formula I as defined above are suitableintermediates for the manufacture of (+)-discodermolide anddiscodermolide analogues.

In particular, a substituted alkene of formula I, wherein all groups R₁,R₂ and R₃ are tert-butyl dimethylsilyl, can be selectively transformedinto a compound of formula I, wherein R₁ is hydrogen and R₂ and R₃ areboth tert-butyl dimethylsilyl, by treatment of the compound withtrifluoroacetic acid in a mixture of tetrahydrofurane and water.Afterwards, the hydrogen atom in the group R₁ can be replaced by a4-methoxybenzyl group by further reacting the compound of formula I witha convenient reagent, e.g., 4-methylchloride or -bromide in the presenceof Ag₂O in a suitable solvent like dimethylformamid at ambienttemperature. Further suitable reagents and reaction conditions aredescribed by T. W. Greene, “Protective Groups in Organic Synthesis”,Wiley, New York 1981, on page 29 and in the references cited there. Verypreferably, the hydrogen atom in the group R₁ is replaced by a4-methoxybenzyl group by reacting a substituted alkene of formula Iwherein R₁ is hydrogen with a compound of formula XVII

wherein m is 1 in a suitable solvent like dichloromethane in thepresence of a suitable catalyst, e.g., samarium triflate or ytterbiumtriflate.

The suitability of the resulting substituted alkene of formula I,wherein R₁ is 4-methoxy-benzyl, R₂ and R₃ are tert-butyl dimethylsilyland R₄ is 4-methoxyphenyl, for the manufacture of (+)-discodermolide wasshown by Amos B. Smith III et al, e.g., in J. Am. Chem. Soc. 2000, 122,8654-8664, In which publication the transformation of such substitutedalkene of formula I (compound “AB” in Scheme 7 on page 8658 and Scheme 9on page 8659) to (+)-discodermolide is disclosed.

The substituted alkene of formula I, wherein R₁, R₂ and R₃ areindependently of each other a protecting group for a hydroxy group orhydrogen and R₄ is phenyl which is unsubstituted or mono-ordisubstituted by alkoxy, is prepared from a sulfonate of formula II,wherein R₁, R₂ and R₃ are all protecting groups for a hydroxy groupwhich protecting groups can be identical or different, R₄ has themeaning as defined for the compound of formula I and R₅ is alkyl or arylwhich is unsubstituted or substituted by alkyl, which sulfonate isreduced, for example, with LiAlH₄, under conditions which are known assuch, e.g. by addition of LiAlH₄ to a solution of the compound offormula II In a suitable solvent at a temperature between −100 and −25°C., e.g. −78° C. Suitable solvents are, e.g., diethyl ether, diglmneand, in particluar, tetrahydrofuran. The reduction can be accomplished,e.g., alternatively with NaBH₄ in a polar aprotic solvent, with LlEt₃BH,with Bu₃SnH—NaI or with NaI and Zn in 1,2-dimethoxyethane.

The reduction of the carboxylic ester of the formula III wherein R₁, R₂and R₃ are all protecting groups for a hydroxy group which protectinggroups can be identical or different, R₆ is alkyl or arylalkyl, and R₄is phenyl which is unsubstituted or mono-or disubstituted by alkoxy,furnishing an alcohol of the formula IV wherein R₁ to R₄ have themeanings as defined for the compound of formula III, is known as suchand can be carried out utilizing reagents like LiBH₄, (isobutyl)₂AlH,lithium triethylborohydride, BH₃—S(methyl)₂ in refluxingtetrahydrofurane, triethoxysilane or sodium in ethanol. Preferably thereaction is carried out using LiAlH₄ in a suitable solvent liketetrahydrofurane.

The alcohol of the formula IV wherein R₁, R₂ and R₃ are all protectinggroups for a hydroxy group which protecting groups can be identical ordifferent, and R₄ is phenyl which is unsubstituted or mono- ordisubstituted by alkoxy, is reacted with a compound of formula V whereinR₅ is alkyl or aryl which is unsubstituted or substituted by alkyl, andHal represent halogen, to a sulfonate of formula II wherein R₁, R₂, R₃and R₄ have the meanings as defined for the alcohol of formula IV and R₅is alkyl or aryl which is unsubstituted or substituted by alkyl, underconditions known as such. Preferably, the reaction is carried out in thepresence of a base, e.g. pyridine, in a suitable inert solvent.

A compound of formula III, wherein R₁ and R₂ are protecting groups for ahydroxy group which protecting groups can be identical or different, R₃is hydrogen and R₆ is alkyl or arylalkyl, and R₄ is phenyl which isunsubstituted or mono-or disubstituted by alkoxy, can also be reacted toa compound of formula I wherein R₁, R₂ and R₄ have the same meaning asin the compound of formula III and R₃ is a protecting group for ahydroxy group in a one-flask synthesis, i.e. without isolating theintermediates described herein.

Preparation of a Compound of Formula VII

A compound of formula VII, wherein R₃ is hydrogen, R₄ is phenyl which isunsubstituted or mono-or disubstituted by alkoxy, and R₆ is alkyl orarylalkyl is obtained, e.g., by reacting an aldehyde of formula XII

wherein R₄ is phenyl which is unsubstituted or mono-or disubstituted byalkoxy with a compound of formula XIII,CH₃CO₂R₆  (XIII)wherein R₆ is alkyl or arylalkyl, in a convenient solvent, inparticular, tetrahydrofurane, in the presence of a strong base,preferably lithium diisopropylamide (LDA), and optionallyN,N,N′,N′,N″,N″-hexamethylphosphotriamide (HMPTA) and a chiral mediatoror catalyst, at a temperature between −100° C. and −0° C., e.g., −78° C.

An aldehyde of formula XII wherein the radical R₄ is phenyl which isunsubstituted or mono- or disubstituted by alkoxy is prepared by aconventional oxidation reaction, e.g., by a Swern oxidation, of analcohol of formula XIV,

wherein R₄ has the meaning as defined for a compound of formula XII.Preferably, oxalyl chloride in a suitable solvent, e.g.,dichloromethane, is mixed with dimethylsulfoxide in the same solvent andthe alcohol of formula XIV is then added at a temperature between about−50° C. and −100° C., e.g., −78° C. Afterwards, a suitable base,especially diisopropylethylamine, is added at the same temperature.

An alcohol of formula XIV wherein R₄ is phenyl which is unsubstituted ormono- or disubstituted by alkoxy is prepared from an acetal of formulaVIII wherein R₁ and R₂ together represent methyliden substituted byphenyl which phenyl group is mono- or disubstituted by alkoxy byreacting the latter compound with LiAlH₄ in a suitable solvent,especially tetrahydrofurane, at a temperature between about −50° C. and−100° C., e.g., −78° C.

An acetal of formula VIII wherein R₁ and R₂ together representmethyliden substituted by phenyl which phenyl group is mono- ordisubstituted by alkoxy can be obtained by two different syntheticroutes:

(a) An aldehyde of formula XV

wherein n is 1 or 2, is first reacted with a ketone of formula XVI

wherein Ph denotes phenyl in a suitable solvent, e.g. dichloromethane inthe presence of a more than equimolar amount of dibutylboryltriflate anda base, preferably, diisopropylethylamine, at a temperature between −15°C. and +15° C., e.g. 0° C., to furnish an oxazolidinone of formula VIII,

wherein R₁ is benzyl which is mono- or disubstituted by alkoxy, and R₂is hydrogen.

Such oxazolidinone of formula VIII is further transformed into acorresponding compound of formula VIII wherein R₂ is a protecting groupfor a hydroxy group which protecting group is not detached byhydrogenolysis, e.g., tert-butyl-dimethylsilyl, by reaction with areagent capable to introduce such protecting group, e.g., by reactionwith tert-butyl-dimethylsilyl-triflate in a suitable solvent liketoluene, chloroform or dichloromethane in the presence of a base, e.g.2,6-lutidine.

Hydrogenolysis of the obtained silyl-protected compound of formula VIII,e.g., by reaction of such compound with hydrogen in the presence of acatalyst like palladium on charcoal using an alcohol as solvent,provides a compound of formula VIII, wherein R₁ is hydrogen and R₂ is aprotecting group for a hydroxy group as defined before.

In an alternative embodiment of the invention a compound of formulaVIII, wherein R₁ is hydrogen and R₂ is a protecting group for a hydroxygroup is provided by the following route.

A compound of formula XVI as defined above is first reacted withmethacrolein in a suitable solvent, e.g. dichloromethane in the presenceof a more than equimolar amount of dibutylboryltriflate and a base,preferably, diisopropylethylamine, at a temperature between −15° C. and−90° C., preferably about −75 to −80° C., to furnish an oxazolidinone offormula XVIII,

wherein Ph denotes phenyl and R₂ is hydrogen.

Said oxazolidinone of formula XVIII is then further transformed into acorresponding compound of formula XVIII wherein R₂ is a protecting groupfor a hydroxy group, e.g., tert-butyl-dimethylsilyl, by reaction with areagent capable to introduce such protecting group, e.g., by reactionwith tert-butyl-dimethylsilyl-triflate In a suitable solvent liketoluene, chloroform or dichloromethane in the presence of a base, e.g.2,6-lutidine.

Finally, the obtained oxazolidinone of formula XVIII wherein R₂ is aprotecting group for a hydroxy group is reacted with thexyl borane, or,preferably, 9-BBN (9-borabicyclo[3.3.1]-nonane) in a suitable solvent,e.g. tetrahydrofurane, at a temperature between −5° C. and +35° C. inorder to furnish the compound of formula VIII, wherein R₁ is hydrogenand R₂ is a protecting group for a hydroxy group.

The compound of formula VIII, wherein R₁ is hydrogen and R₂ is aprotecting group for a hydroxy group is then contacted with atrichloroacetimidate of formula XVII

wherein m is 1, 2 or 3, in a suitable solvent like dichloromethane inthe presence of a suitable catalyst, e.g., samarium triflate orytterbium triflate, in order to furnish a compound of formula VIII,wherein R₁ is benzyl which is mono- or disubstituted by alkoxy and R₂ isa protecting group for a hydroxy group which protecting group is notdetached by hydrogenolysis.

Such compound of formula VIII is then further reacted with a reagentcapable of detaching the protecting group R₂ under conditions leavingthe group R₁ unchanged, which conditions are known as such. For example,if R₂ is tert-butyl-dimethylsilyl, the reagent capable of detaching suchgroup can be aqueous hydrogenfluoride to be combined with the compoundof formula VII in acetonitrile or another suitable lower alkyl cyanide.The reaction provides a compound of formula VII wherein R₁ is benzylwhich is mono- or disubstituted by alkoxy and R₂ is hydrogen.

The desired acetal of formula VIII wherein R₁ and R₂ together representmethyliden substituted by phenyl which phenyl group is mono- ordisubstituted by alkoxy is obtained by treating such compound of formulaVII wherein R₁ is benzyl which is mono-or disubstituted by alkoxy and R₂is hydrogen with DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) whichreaction can be carried out in a suitable solvent like dichloromethaneat a temperature between −10° C. and +10° C., preferably at about 0° C.

(b) The oxazolidinone of formula XVIII, wherein Ph denotes phenyl and R₂is hydrogen, obtained as described above, can also be reacted withthexyl borane, or, preferably, 9-BBN (9-borabicyclo[3.3.1]nonane) in asuitable solvent, e.g. tetrahydrofurane, at a temperature between −5° C.and +35° C. without prior protection of the hydroxy group present in thecompound. The reaction product is a compound of formula VIII wherein R₁and R₂ are both hydrogen. Such product can be further reacted in asuitable solvent, like dichloromethane, at a temperature, e.g., between15° C. and 30° C. in the presence of a suitable acid like toluenesulphonic acid, camphor sulfonic acid or, preferably, Amberlyst 15 witha compound of formula XIXa

wherein q is 0, 1 or 2, and R_(x) and R_(y) are lower alkyl furnishingthe desired acetal of formula VIII wherein R₁ and R₂ together representmethyliden substituted by phenyl which is mono- or disubstituted byalkoxy.

Alternatively, a compound of formula VIII wherein R₁ and R₂ are bothhydrogen can also be transferred into an acetal of formula VIII whereinR₁ and R₂ together represent methyliden substituted by phenyl which ismono- or disubstituted by alkoxy by reaction with a compound of formulaXIXb

wherein q is 0, 1 or 2, in a suitable solvent, like dichloromethane orbenzene, under reaction conditions known as such, especially at thereflux temperature of the solvent optionally in the presence of areagent that reacts with the water that is obtained in the course of thereaction, like dicyclohexyl carbodilmide.

A further alternative for obtaining an acetal of formula VIII wherein R₁and R₂ together represent methyliden substituted by phenyl which ismono-or disubstituted by alkoxy starting from a compound of formula VIIIwherein R₁ and R₂ are both hydrogen constitutes the reaction of thelatter compound with a compound of formula XIXc

wherein q is 0, 1 or 2 and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ) in a suitable solvent, e.g. dichloromethane, under reactionconditions known as such.

The δ-valerolactol of the formula X and the δ-valerolacton of theformula XX

wherein in both cases R₂ is a protecting group for a hydroxy group aresuitable starting materials for the synthesis of the compounds offormula VI and VII. For example, the compound of formula (XX) wherein R₂is a protecting group for a hydroxy group can be reacted with LiOH and areagent capable of introducing a protecting group for a hydroxy group R₂in a suitable solvent to provide a compound of formula XXV

wherein R₁ and R₂ are independently of each other a protecting group fora hydroxy group. Such compound can then be reduced with reagents knownas such, e.g. NaBH₄ together with AlCl₃ in diglyme, BH₃ intetrahydrofurane, LiAlH(O-methyl)₃ in tetrahydrofurane, AlH₃ indiethylether, LiAlH₄ in diethylether or diisobutyl aluminium hydride intetrahydrofurane, in all cases under conditions known such, to furnish acompound of formula XI

wherein R₁ and R₂ have the meanings as defined for the compound offormula XXV.

Said lactol of formula X is obtained by reacting said lacton of formulaXX with DIBAH (diisobutylaluminium hydride) in a suitable solvent, liketetrahydrofurane, at a temperature between about −85 to −70° C.

The lacton of formula XX wherein R₂ is a protecting group for a hydroxygroup is the product of the reaction of a compound of formula VIIIwherein R₁ is hydrogen and R₂ is a protecting group for a hydroxy groupwith a catalytic amount of a potassium alcoholate, e.g. potassiumtert-butanolate, in a suitable solvent, e.g. tetrahydrofurane, at atemperature between about −10° C. and +10° C., e.g. 0° C.

Alternatively, the lacton of formula XX wherein R₂ is a protecting groupfor a hydroxy group can be prepared by the following synthetic route:

An aldehyde of formula XV wherein n is 1 or 2, is first reacted with aketone of formula XXI

wherein Ph denotes phenyl, in a suitable solvent, e.g. dichloromethanein the presence of a more than equimolar amount of dibutylboryltriflateand a base, preferably, diisopropyl-ethylamine, at a temperature between−15° C. and +15° C., e.g. 0° C., to furnish an oxazolidinone of formulaIX,

wherein Ph denotes phenyl and R′ is benzyl which is unsubstituted ormono-or disubstituted by alkoxy and R₂ is hydrogen.

Such oxazolidinone of formula IX is then further transformed into acorresponding compound of formula IX wherein R₂ is a protecting groupfor a hydroxy group which protecting group is not detached byhydrogenolysis, e.g., tert-butyl-dimethylsilyl, by reaction with areagent capable to introduce such protecting group, e.g., by reactionwith tert-butyl-dimethylsilyl-triflate in a suitable solvent liketoluene, chloroform or dichloromethane in the presence of a base, e.g.2,6-lutidine.

Hydrogenolysis of the obtained protected compound of formula IX, e.g.,by reaction of such compound with hydrogen in the presence of a catalystlike palladium on charcoal using an alcohol as solvent, provides acompound of formula IX, wherein R₁ is hydrogen and R₂ is a protectinggroup for a hydroxy group as defined before.

Such compound of formula IX, wherein R₁ is hydrogen and R₂ is aprotecting group for a hydroxy group which protecting group is notdetached by hydrogenolysis provides the desired lacton XX by reactionwith H₂O₂ in a mixture of a suitable solvent, e.g. tetrahydrofurane,with water in the presence of LiOH at a temperature between −15° C. and+15° C., e.g. 0° C.Preparation of the Allyl Halide of Formula VI

wherein R₁ and R₂ are protecting groups for a hydroxy group whichprotecting groups can be identical or different and X is halogen isobtained by the following reaction steps:

The oxazolidinone of formula VIII, wherein Ph denotes phenyl and whereinR₁ and R₂ are both hydrogen, obtained as described above, is transformedinto a corresponding compound of formula VIII wherein R₁ and R₂ are bothprotecting groups for a hydroxy group which protecting groups are notdetachable under the reaction conditions of the following reaction stepsproviding the desired compound of formula VI, preferably a silylprotecting group for a hydroxy group, e.g., tert-butyl-dimethylsilyl, byreaction with a reagent capable to introduce such protecting groups,e.g., by reaction with tert-butyl-dimethylsilyl-triflate in a suitablesolvent like toluene, chloroform or dichloromethane in the presence of abase, e.g. 2,6-lutidine.

The latter compound of formula VIII is then reacted with a suitablereduction reagent, preferably LiBH₄, in a suitable solvent, e.g. amixture of tetrahydrofuranee and water, at a temperature between about−5° C. and +30° C. to provide an alcohol of the formula XI

wherein both R₁ and R₂ represent a protecting group for a hydroxy groupwhich protecting group is not detachable under the reaction conditionsof the following reaction steps providing the desired compound offormula VI, preferably a silyl protecting group.

Such alcohol of formula XI is then oxidized by a suitable reagent,preferably via Swern oxidation, to the corresponding aldehyde of formulaXXII

wherein R₁ and R₂ are as defined above for a compound of formula XI.Wittig olefination with a phosphonate of formula XXIII

wherein R₇ is alkyl or arylalkyl and R₈ and R₉ are independently of eachother alkyl which is unsubstituted or substituted by halogen, preferablyfluorine, provides an α,β-unsaturated carboxylic acid ester of formulaXXIV

wherein R₁ and R₂ are as defined above for a compound of formula XI andR₇ is alkyl or arylalkyl. The reaction is preferably accomplished intetrahydrofurane in the presence of the base potassiumhexamethyldisilazane and 18-crown-6.

Said compound of formula XXIV is further reacted with DIBAH or anotherreagent, especially a reagent disclosed herein, capable of transforminga carboxylic ester into an alcohol, in a suitable solvent, for example,in the case of DIBAH in dichloromethane, to furnish an allylic alcoholof formula VI wherein R₁ and R₂ are protecting groups for a hydroxygroup which protecting groups can be identical or different and X ishydroxy.

Finally, the allylic alcohol of formula VI is transformed into thedesired allylic halide of formula VI, preferably an allylic iodide byreaction with iodine in the presence of triphenylphosphine and imidazolein a suitable solvent, e.g., a mixture of diethylether and a lower alkylnitrile.

The skilled person will understand that the reaction conditions givenabove can be replaced by analogous reaction conditions that are inprinciple known in the art. Furthermore, a person skilled in the artwill be aware of suitable protecting groups of hydroxy that can replacethe protecting groups used in the specific Examples below and how toattach such groups to free hydroxy groups present in the compoundsdescribed hereinbefore and hereinafter, especially in a compound offormula I, IV, VIII or IX, and how to detach such groups, if desired. Inaddition, the skilled person will be able to select the appropriatespecific reaction conditions for the reaction steps given hereinbelowand hereinafter where reactions are described generally herein. Allthose reaction conditions are included in the scope of the presentinvention.

The protection of hydroxy groups by protecting groups, the protectinggroups themselves, and their cleavage reactions are described forexample in standard reference works, such as J. F. W. McOmie,“Protective Groups in Organic Chemistry”, Plenum Press, London and NewYork 1973, in T. W. Greene, “Protective Groups in Organic Synthesis”,Wiley, New York 1981, in “The Peptides”; Volume 3 (editors: E. Gross andJ. Melenhofer), Academic Press, London and New York 1981, In “Methodender organischen Chemie” (Methods of organic chemistry), Houben Weyl, 4thedition, Volume 15/I, Georg Thieme Verlag, Stuttgart 1974, in H. -D.Jakubke and H. Jescheit, “Aminosauren, Peptide, Proteine” (Amino acids,peptides, proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel1982, and in Jochen Lehmann, “Chemie der Kohlenhydrate: Monosaccharideund Derivate” (Chemistry of carbohydrates: monosaccharides andderivatives), Georg Thieme Verlag, Stuttgart 1974.

The following examples are for purposes of illustration only and are notintended to limit in any way the scope of the instant invention.Starting materials can be purchased or prepared by the methods mentionedhereinafter.

Abbreviations: aqu. aqueous 9-BBN 9-borabicyclo[3.3.1]nonane brinesaturated sodium chloride solution bu butyl DIBAH diisobutylaluminiumhydride DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DMSO dimethylsulfoxide Et ethyl EtOAc ethyl acetate FC flash-chromatography h hour(s)HMPA N,N,N′,N′,N″,N″-hexamethylphosphotriamide HRMS high resolution massspectrometry K Kelvin KHMDS potassium hexamethyldisilazane min minute(s)m.p. melting point Me methyl MS mass spectrometry MS(EI) electrosprayionisation mass spectrum Ph phenyl PTLC preparative thin layerchromatography RT room temperature sat. saturated TBDMStert-butyl-dimethylsilyl TBME tert-butyl methyl ether TBSOTftert-butyl-dimethylsilyl-trifluoromethanesulfonate Tftrifluoromethanesulfonate THF tetrahydrofurane Abbreviations for th NMRspectra data b broad d doublet J coupling constant m multiplet q quartets singlet t triplet ppm parts per million

EXAMPLE 1 (4R)-4-Benzyl-(N)-[(2R, 3S,4S)-5-(4-methoxybenzyloxy)-2,4-dimethyl-3-(tert-butyl-dimethylsilyloxy)-valeryl]-oxazolidin-2-one

The alcohol from stage 1.1 (1.36 g, 3.1 mmol) is dissolved in 10 mL ofCH₂Cl₂ under an atmosphere of argon and cooled to 0° C. 2,6-Lutidine(0.49 mL, 4.0 mmol, 1.3 eq.) is added followed by dropwise addition ofTBSOTf (0.78 mL, 3.4 mmol, 1.1 eq.). The reaction mixture is stirred for30 min, poured onto ice water and extracted with hexane. The organiclayer is washed with 1N HCl, sat. aqu. NaHCO₃ and sat. aqu. NaCl, thendried over MgSO₄ and concentrated in vacuo to give the title compound asa colorless oil.

Stage 1.1: A solution of (R)-4-benzyl-(N)-propionyloxazolidin-2-one(Aldrich, 336 mg, 1.44 mmol) in 3.0 mL dichloromethane is treated with a1.0 M solution (1.6 mL, 1.6 mmol) of Bu₂BOTf at 0° C. under anatmosphere of argon. To the resulting brown-red mixture 0.30 mL (1.7mmol) of diisoproylethylamine is added to give a colorless, clearsolution, which is stirred a 0° C. for 1 h. Then a solution of(S)-3-(4-methoxybenzyloxy)-2-methyl-propionaldehyde (Aldrich, 300 mg,1.44 mmol) dissolved in 1.5 mL of CH₂Cl₂ is added slowly at −78° C. Thereaction mixture is stirred at this temperature for 60 min and at 0° C.for 45 min. Phosphate buffer pH 7.0 is added followed by extraction (3times) with TBME. The combined organic layers are washed with sat. aqu.NaCl solution, dried over MgSO₄ and concentrated in vacuo. The residueis redisolved in 5 mL of methanol and treated with 2 mL of aqu. H₂O₂(30%) at 0° C. After stirring for 1 hour the volatiles are removed invacuo and the aqueous phase is extracted with TBME (3 times). Thecombined organic layers are washed with sat. NaHCO₃ and brine, driedover MgSO₄, and concentrated in vacuo. After chromatographicpurification (SiO₂, heptane/ethylacetate 2:1) the desired alcohol isobtained as a colorless oil.

EXAMPLE 2 (4R)-4-Benzyl-(N)-[(2R, 3S,4S)-5-hydroxy-2,4-dimethyl-3-(tert-butyl-dimethylsilyloxy)-valeryl]-oxazolidin-2-one

A solution of 132 mg (0.24 mmol) of the TBDMS ether from Example 1 in3.0 mL of methanol is hydrogenated in the presence of a catalytic amountof Pd/C under 1 bar of hydrogen atmosphere for 6 h at 23° C. Afterfiltration of the reaction mixture through a pad of celiflock which iswashed 3 times with ethylacetate, concentration in vacuo and FC(SiO₂,hexanes/EtOAc 1:1), the title compound is obtained as a colorless oil.¹H-NMR (CDCl₃, 300 MHz, 300K) δ 7.32-7.05 (m, 5H), 4.62-4.52 (m, 1H),4.12 (d, J=6.0 Hz, 1H), 4.12-4.0 (m, 2H), 3.50 (dd, J=12.0, 5.3 Hz, 1H),3.42 (dd, J=12.0, 6.8 Hz, 1H), 3.19 (dd, J=13.5, 3.7 Hz, 1H), 2.70 (dd,J=13.5, 9.0 Hz, 1H), 1.9-1.85 (m, 1H), 1.65-1.45 (br m, 1H), 1.20 (d,J=8.3 Hz, 3H), 0.92 (d, J=7.5 Hz, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.00(s, 3H). MS (EI) m/Z 458 (100, [M+Na]⁺).

EXAMPLE 3 (1RS, 2R, 3S,4S)-5-Hydroxy-2,4-dimethyl-3-tert-butyl-dimethylsilyloxy-δ-valerolactol

The lactone of stage 3.1 (1.00 g, 3.87 mmol) is dissolved in 40 mL oftoluene and 3.10 mL (4.65 mmol) of DIBAH (1.5 M in toluene) is addedover 10 min at −78° C. After 30 min at −78° C., the reaction mixture isquenched by addition of 2 mL of MeOH. The resulting mixture is poured onaqu. sat. NH₄Cl and the two layers are separated. The aqu. layer isextracted (3 times) with EtOAc. The combined organic phases are washedsuccessively with 10% aqu. H₂SO₄, sat. aqu. NaHCO₃ and sat. aqu. NaCl,dried over MgSO₄ and concentrated in vacuo to give the title compound asa colorless oil. ¹H-NMR (CDCl₃, 300 MHz, 300K, mixture of anomers,ratio=4.2:1.0) major anomer: δ 4.68 (br s, 1H); 3.72 (dd, J=11.2, 0.8Hz, 1H); 3.62 (br m, 1H), 3.32 (dd, J=11.2, 5.6 Hz, 1H); 2.02-1.85 (twom, 2H), 0.93 (d, J=7.1 Hz, 3H), 0.87 (s, 9H), 0.75 (d, J=7.5 Hz, 3H),0.04 (s, 3H), 0.01 (s, 3H); minor anomer: δ 5.00 (d, J=1.9 Hz, 1H),3.80-3.67 (m, 1H, obscured by one signal from the major anomer), 3.43(dd, J=11.3, 7.1 Hz, 1H), 2.05-1.80 (two m, 2H), 0.90 (d, J=7.3 Hz, 3H),0.84 (s, 9H), 0.82 (d, J=7.5 Hz, 3H), 0.00 (s, 3H), ?0.3 (s, 3H); MS(EI) m/z244 (7, [M−O]⁺), 204 (55, [M−C(CH₃)₃]⁺), 145 (100,[M−Si(CH₃)₂(CH₃)₃]⁺).

Stag 3.1: A solution of the alcohol from Example 2 (43 mg, 0.1 mmol) in1.5 mL of THF/H₂O (3:1) is treated with 40 μl (0.4 mmol, 4.0 eq.) ofH₂O₂ (30%) followed by 8 mg (0.2 mmol, 2.0 eq.) of LiOH monohydrate at0° C. After stirring for 40 min, 0.3 mL of a 1.5 M aqu. solution ofNa₂SO₃ is added. The reaction is quenched with sat. aqu. NaHCO₃ andextracted with TBME. The ether layer is washed with sat. aqu. NaHCO₃solution twice. The combined aqu. extracts are acidified (pH 3) with 1 NHCl and extracted with ethylacetate (3 times). The organic layers arecombined, dried over MgSO₄ and concentrated in vacuo to give the desiredlactone as a colorless crude oil containing some oxazolidinone as themajor impurity. ¹H-NMR DMSO-d⁶, 400 MHz, 300K) δ 4.20 (dd, J=11.5, 4.0Hz, 1H), 4.07 (dd, J=11.5, 8.4 Hz, 1H), 3.83 (dd, J=5.3, 2.8 Hz, 1H),2.47 (qd, J=7.8, 5.3 Hz, 1H), 2.28-2.15 (m, 1H), 1.20 (d, J=7.8 Hz, 3H),0.90 (d, J=7.1 Hz, 3H), 0.88 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H). MS(EI) m/z 539 (30, [M+2 Na]⁺), 322 (55, [M+CH₃CN]⁺).

EXAMPLE 4 (4R)-4-Isopropyl-5,5-diphenyl-(N)-[(2R, 3S,4S)-5-hydroxy-2,4-dimethyl-3-(tert-butyl-dimethylsilyloxy)-valeryl]-oxazolidin-2-one

To a solution of 7.67 g (14.7 mmol) of the TBDMS ether of stage 4.2 in60 mL of THF at 0° C. under an atmosphere of argon is added 3.59 g (29.4mmol) of 9-BBN in 50 mL of THF. After 15 min at 0° C. the reactionmixture is warmed to ambient temperature with stirring for 5 h. Themixture is recooled to 0° C. and quenched with 19.4 mL each of 1:1 (v/v)EtOH/THF, aqu. pH 7 phosphate buffer, and 35% aqu. hydrogen peroxide.After 30 min, the solution is again warmed to ambient temperature andstirred for 15 h. Heptane (150 mL) and 20% aqu. NaHSO₃ (120 mL) areadded and the aqu. layers are extracted with heptane (2×100 mL). Thecombined organic layers are washed with sat. aqu. NaCl (1×100 mL), driedover MgSO₄, filtered, and concentrated in vacuo. Purification by FC(SiO₂, hexane/AcOEt 4:1) gives the title compound as a colorless oilwhich crystallizes upon conservation at 4° C. ¹H-NMR (CDCl₃, 300 MHz,300K) δ 7.55-7.15 (4 m, 10H), 5.27 (d, J=3.5 Hz, 1H), 3.95 (dd, J=9.4,2.5 Hz, 1H), 3.76 (qd, J=9.4, 6.9 Hz, 1H), 2.91 (dd, J=12.0, 4.9 Hz,1H), 2.49 (dd, J=12.0, 7.5 Hz, 1H), 1.79 (heptuplet, J=6.8, 3.5 Hz, 1H),1.72-1.65 (br s, 1H), 1.33-18 (m, 1H), 1.23 (d, J=6.9 Hz, 3H), 0.83, (d,J=6.8 Hz, 3H), 0.81 (s, 9H), 0.72 (d, J=6.8 Hz, 3H), 0.58 (d, J=7.1 Hz,3H), 0.00 (s, 6H).

The title compound is converted to the lactone of stage 3.1 using thefollowing procedure:

The title compound (2.08 g, 3.85 mmol) is dissolved in 40 mL of THF anda solution of t-BuOK (1.5 M in THF, 77 μL, 77 μMol) is added at 0° C.under an atmosphere of argon. The clear, colorless solution is allowedto stir for 1 h and to warm up to 23° C. A white precipitate is formed.The reaction mixture is diluted with 50 mL of hexane and is filtered.The residue is washed with aqu. sat. NaCl. The filtrate is collected andthe two layers separated. The organic layer is dried over MgSO₄ andpartially concentrated in vacuo. A white precipitate is formed duringthe concentration. The mixture is filtered and the residue is washedwith 5 mL of hexane. The filtrate is collected and concentrated in vacuoto give the pure lactone of stage 3.1 as a colorless oil whichsolidified upon conservation at 4° C. providing a solid having a m.p. of53-54° C.

Stage 4.1: A solution of 14.9 mL (87 mmol, 1.45 eq.) ofdiisoproylethylamine in 30 mL of CH₂Cl₂ under an atmosphere of argon istreated sequentially at −5° C. over 10 min with a 1.0 M solution (78 mL,78 mmol, 1.3 eq.) of Bu₂BOTf in CH₂Cl₂ and at −78° C. over 15 min with asolution of (R)-4-isopropyl-5,5-diphenylpropionyloxazolidin-2-one (20.2g, 60 mmol; prepared according to T. Hintermann, D. Seebach, Helv. Chim.Acta 1998, 81, 2093) in 60 mL of CH₂Cl₂ to give a clear orange solution.After 10 min at −78° C., the solution is warmed to 0° C. with stirringfor 1 h, after which it is recooled to −78° C. again. A solution ofmethacrolein (14.8 mL, 180 mmol, 3 eq.) dissolved in 20 ml of CH₂Cl₂ isthen added slowly over a period of 30 min. After 30 further minstirring, the reaction mixture is warmed to 0° C. with stirring for 1 h.Phosphate buffer pH 7.0 (60 mL), MeOH (180 mL) and MeOH/35% H₂O₂ (2:1v/v, 180 mL) are added sequentially at 0° C. After stirring for 3 h atambient temperature, the mixture is recooled to 0° C. and treated with40% aqu. NaHSO₃ (80 mL). The volatiles are removed in vacuo and the aqu.phase is extracted with toluene (3×200 mL). The combined organic layersare washed with 1N HCL (60 mL), sat. aqu. NaHCO₃ (60 mL) and sat. aqu.NaCl (60 mL) solutions, dried over MgSO₄, filtered, and concentrated invacuo to give 28.6 g of the desired alcohol as slightly yellowish crudesolid residue, a sample of which is purified by FC (SiO₂, hexane/AcOEt3:1) to afford the pure alcohol as white crystals with a m.p. of99.5-100.0° C.

Stage 4.2: The crude alcohol of stage 4.1 (13.9 g) is dissolved in 50 mLof CH₂Cl₂ under argon and cooled to 0° C. 2,6-Lutidine (4.9 mL, 42 mmol)is added followed by dropwise addition over 10 min of TBSOTf (7.1 mL, 31mmol). The reaction mixture is stirred for 30 min at 0° C., after which100 mL of hexane and 45 mL of 1N HCL are added sequentially. The aqu.layer is extracted (2 times) with hexane. The combined organic layersare washed with 1N HCl (2 times), sat. aqu. NaHCO₃ and sat. aqu. NaCl,then dried over MgSO₄ and concentrated in vacuo to give 17.7 g of thecrude product as yellow crystals. After recrystallization from 20 mL ofhexane with addition of seed crystals, the desired TBDMS ether isobtained as slightly yellowish crystals with a m.p. of 116° C.

EXAMPLE 5 (4R)-4-Isopropyl-5,5-diphenyl-(N)-[(2R, 3S,4S)-5-hydroxy-2,4-dimethyl-3-(tert-butyl-dimethylsilyloxy)-valeryl]-oxazolidin-2-one

A solution of 110 mg (0.17 mmol) of the TBDMS ether of stage 5.2 in 3.0mL MeOH is hydrogenated in the presence of a catalytic amount of Pd/Cunder 1 bar of hydrogen atmosphere for 5 h at 23° C. After filtration ofthe reaction mixture through a pad of cellflock which is washed 3 timeswith MeOH, concentration in vacuo and FC (SiO₂, hexane/EtOAc 5:1) thetitle compound is obtained as a white solid (physical data see Example4.

Stage 5.1: A solution of(R)-4-isopropyl-5,5-diphenylpropionyloxazolidin-2-one (see stage 4.1;1.00 g, 2.96 mmol) in 7.5 mL of dichloromethane is treated with a 1.0 Msolution (3.55 mL, 3.55 mmol) of Bu₂BOTf at 0° C. under an atmosphere ofargon. To the resulting brown-red mixture 0.66 mL (3.85 mmol) ofdiisoproylethylamine is added to give a colorless, clear solution, whichis stirred a 0° C. for 1 h. Then a solution of(S)-3-(4-methoxybenzyloxy)-2-methyl-propionaldehyde (Aldrich, 616 mg,2.96 mmol) dissolved in 1.0 ml of CH₂Cl₂ is added slowly at −78° C. Thereaction mixture is stirred at this temperature for 60 min and at 0° C.for 60 min. Phosphate buffer pH 7.0 (3.0 mL), MeOH (8.9 mL) and MeOH/30%H₂O₂ (2:1 v/v, 8.9 mL) are added sequentially at 0° C. After stirringfor 1 h at RT, the volatiles are removed in vacuo and the aqu. phase isextracted with TBME (3 times). The combined organic layers are washedwith 1N HCL, sat. aqu. NaHCO₃ and sat. aqu. NaCl solutions, dried overMgSO₄ and concentrated in vacuo. After chromatographic purification(SiO₂, heptane/EtOAc 4:1) the desired alcohol is obtained as a colorlessoil.

Stage 5.2: The alcohol from stage 5.1 (96 mg, 0.18 mmol) is dissolved in5 mL of CH₂Cl₂ under argon and cooled to 0° C. 2,6-Lutidine (31 μL, 0.27mmol) is added followed by dropwise addition of TBSOTf (50 μL, 0.22mmol). The reaction mixture is stirred for 45 min at 0° C., poured ontoice water and extracted with TBME (3 times). The combined organic layersare washed with 1N HCl, sat. aqu. NaHCO₃ and sat. aqu. NaCl, then driedover MgSO₄ and concentrated in vacuo to give the desired product as acolorless oil.

EXAMPLE 6 (4R)-4-Isopropyl-5,5-diphenyl-(N)-[(2R, 3S,4S)-3,5-dihydroxy-2,4-dimethylvaleryl]-oxazolidin-2-on

To a solution of 10.2 g (25.0 mmol) of the allylic alcohol from stage4.1 in 100 mL of THF at 0° C. under an atmosphere of argon, a solutionof 9-BBN (7.56 g, 62.0 mmol, 2.5 eq.) in 130 mL of THF is added over aperiod of 30 min. After 10 min at 0° C. the reaction mixture is warmedto ambient temperature with stirring for 6.5 h. The mixture is recooledto −15° C. and quenched with 78 mL each of 1:1 (v/v) EtOH/THF, aqu. pH 7phosphate buffer, and 35% aqu. hydrogen peroxide. After 30 min, thesolution is again warmed to ambient temperature and stirred for 15 h. A40% aqu. solution of NaHSO₃ (210 g) and heptane (200 mL) are addedsequentially and the aqu. layers are extracted with heptane (2×150 mL).The combined organic layer is washed with 0.2 N NaOH (2×100 mL), sat.aqu. NH₄Cl (1×100 mL), and sat. aqu. NaCl (1×100 mL), dried over MgSO₄,filtered, and concentrated in vacuo. Purification by FC (SiO₂,hexane/AcOEt 1:1) gives 7.38 g of the title compound as a colorless oilwhich crystallizes upon conservation at 4° C. providing a solid with am.p. of 103-104° C.

EXAMPLE 7 (4R)-4-Isopropyl-5,5-diphenyl-(N)-[(2R, 3S,4S)-3,5-bis(tert-butyl-dimethylsilyloxy)-2,4-dimethyl-valeryl]-oxazolidin-2-one

The alcohol of Example 6 (1.10 g, 2.04 mmol) is dissolved in 20 mL ofCH₂Cl₂ under an atmosphere of argon and cooled to 0° C. 2,6-Lutidine(0.28 mL, 2.45 mmol, 1.20 eq.) is added followed by dropwise addition ofTBSOTf (0.49 mL, 2.14 mmol, 1.05 eq.). The reaction mixture is stirredfor 60 min, poured onto 1 N HCl and extracted with heptane (3 times).The organic layer is washed with sat. aqu. NaHCO₃ and sat. aqu. NaCl,then dried over MgSO₄ and concentrated in vacuo to give the titlecompound as a colorless oil which crystallizes upon conservation at 4°C. providing a solid with a m.p. of 104-105° C.

EXAMPLE 8 (2S, 3S,4S)-3,5-Bis(tert-butyl-dimethylsilyloxy)-2,4-dimethyl-pentan-1-ol

A 2.0 M solution of LiBH₄ (6.55 mL, 13.10 mmol) in THF is added to asolution of the bis-TBDMS ether of Example 7 (5.36 g, 8.19 mmol) in 130mL of diethylether and 234 μL (13.02 mmol) of water at 0° C. over aperiod of 10 min. The mixture is allowed to warm to ambient temperatureover night. The chiral auxiliary forms a white crystalline precipitate.Another 73 μL (4.06 mmol) water and 2.05 mL (4.09 mmol) of a 2 M LiBH₄solution are added at 23° C. After additional 6.5 h reaction timefurther 73 μL (4.06 mmol) water and 2.05 mL (4.09 mmol) of a 2 M LiBH₄solution are added at 23° C. and the resulting mixture is stirred overnight. The reaction is quenched by adding 200 mL of 1 N NaOH followed bythe addition of 400 mL ethylacetate. The phases are separated and theaqu. layer is extracted twice with 150 mL ethylacetate. The combinedorganic phases are washed with brine (250 mL), dried over MgSO₄ andconcentrated in vacuo. The residue is suspended in 80 mL heptane,stirred at 0° C. for 1.5 h and filtered. The obtained cake is washedwith cold heptane (75 mL) and dried at 50° C. in vacuo to give recycledauxiliary. The combined filtrates are concentrated to provide the crudetitle compound as a colorless oil.

cis-(4S, 5R,6S)-5,7-Bis(tert-butyl-dimethylsilyloxy)-2,4,6-trimethyl-hept-2-en-1-yliodidcan be obtained from the title compound by the following procedure:

Stage 8.1: A solution of 0.455 mL (5.30 mmol) oxalylchloride in 20 mLCH₂Cl₂ is treated with a solution of 0.75 mL (10.6 mmol) DMSO in 1.0 mLCH₂Cl₂ at −78° C. After 15 min a solution of the title compound (1.0 g,2.65 mmol) in 8 mL CH₂Cl₂ is added dropwise over a period of 30 min.Et₃N (2.3 mL, 15.9 mmol) is added over 12 min and the reaction mixtureis allowed to warm to room temperature. After additional stirring for 30min 40 mL TBME and 50 mL of a sat. NH₄Cl solution are added. The aqu.layer is separated and extracted twice with 30 mL TBME. The combinedorganic layers are washed with 50 mL brine, dried over MgSO₄ andconcentrated under reduced pressure. The residual oil is purified by FC(heptane/ethylacetate 100:1.5) to give the desired aldehyde as acolorless oil. ¹H-NMR (CDCl₃, 300 MHz, 300K) δ=9.67 (s, 1H), 4.19 (dd,J=6.6, 3.2 Hz, 1H), 3.52 (ddd, J=25.7, 10.0, 5.7 Hz, 2H), 2.44-2.47 (m,1H), 1.78-1.87 (m, 1H), 1.07 (d, J=7.0 Hz, 3H), 0.87 (d, J=7.0 Hz, 3H),0.86 (s, 9H), 0.82 (s, 9H), 0.03 (s, 3H), 0.00 (2s, 6H), −0.05 (s, 3H).

Stage 8.2: A solution of 2-[bis-(2,2,2-trifluoroethyl)]-phosphonopropionic acid ethyl ester (0.948 g, 2.74 mmol, prepared analog to theprocedure described in Synthesis 1986, 16(11) 1285-1295) and 18-crown-6(2.0 g, 10.0 mmol) in 20 ml THF is treated with 5.5 mL (2.74 mmol) of a0.5 M solution of KHMDS In toluene at −78° C. After 5 min a solution ofthe aldehyde of stage 8.1 (1.029 g, 2.74 mmol) in 8 ml THF is addeddropwise over 15 min. The pale yellow reaction mixture is stirred foradditional 45 min at 0° C. Then 20 mL TBME and 20 mL of a sat. NH₄Clsolution is added followed by the addition of 10 mL of water. The layersare separated and the aqu. phase is extracted with 90 mL TBME. Thecombined organic layers are washed with brine and concentrated in vacuo.The residue is suspended in 10 mL of n-heptane, stirred for 10 min andfiltered. The filtrate is concentrated to give the desiredcis-ethylester.

Stage 8.3: A solution of the ethylester of stage 8.2 (97 mg, 0.21 mmol)in 5 mL of CH₂Cl₂ is treated with a 1.5 M solution in toluene of DIBAH(0.42 mL, 0.63 mmol, 3.0 eq.) at −78° C. under an atmosphere of argon.The reaction mixture is warmed to 0° C. with stirring for 30 min, afterwhich it is quenched by addition of a 10% aqu. solution of H₂SO₄. Theaqu. layer is extracted (3 times) with EtOAc. The combined organiclayers are washed with sat. aqu. NaHCO₃ and sat. aqu. NaCl, then driedover MgSO₄, filtered, and concentrated in vacuo. Purification by FC(SiO₂, hexane/AcOEt 9:1) provides the desired allylic alcohol as acolorless oil.

Stage 8.4: A solution of the allylic alcohol of stage 8.3 (59 mg, 0.14mmol) in 4 mL of a mixture of CH₃CN/Et₂O (1:3 v/v) is treated with PPh₃(55 mg, 0.21 mmol, 1.5 eq.), imidazole (14 mg, 0.21 mmol, 1.5 eq.), andiodine (53 mg, 0.21 mmol, 1.5 eq.) at 0° C. under an atmosphere ofargon. The resulting yellow suspension is stirred for 30 min at 0° C.,after which a sat. aqu. solution of NaHSO₃ is added. The aqu. layer isextracted with TBME (3 times). The combined organic layers are washedwith 1N HCl, sat. aqu. NaHCO₃ and sat. aqu. NaCl, then dried over MgSO₄,filtered, and concentrated in vacuo. Purification by FC (SiO₂,hexane/AcOEt 20:1) gives the desired allylic iodide as a slightlyyellowish oil.

EXAMPLE 9 (4R)-4-Isopropyl-5,5-diphenyl-(N)-[(2R, 3S,4s)-5-(4-methoxybenzyloxy)-2,4-dimethyl-3-(tert-butyl-dimethylsilyloxy)-valeryl]-oxazolidin-2-one

A solution of the alcohol of Example 4 (3.61 g, 6.69 mmol) in 55 mL ofCH₂Cl₂ is treated with SmOTf₃ (160 mg, 0.27 mmol, 4 mol %) at 23° C.under an atmosphere of argon. The slightly turbid solution is cooled to−20° C. and treated by dropwise addition over a period of 45 min with asolution of 4-methoxybenzyl-2,2,2-trichloroacetimidate (2.27 g, 8.03mmol., 1.20 eq., prepared according to the method described inTetrahedron 1999, 55, 1607-1630) in 55 mL of CH₂Cl₂. At the end of theaddition, the resulting reaction mixture is stirred at −20° C. for 30min, after witch it is warmed to −10° C. and treated with 50 mL ofwater. The layers are separated. The organic layer is washed with 0.5 NNaOH (50 mL) and aqu. sat. NaCl (50 mL), dried over MgSO₄, filtered andconcentrated in vacuo. After purification by FC (SiO₂, hexane/AcOEt5:1), the title compound is obtained as a colorless oil. ¹H-NMR (CDCl₃,300 MHz, 300K) δ=7.50-7.22 (m, 12H), 6.83-6.78 (m, 2H), 5.39 (d, J=3.3Hz, 1H), 4.00-3.83 (m, 4H), 3.78 (s, 3H), 3.08 (dd, J=9.4, 6.5 Hz, 1H),2.72 (dd, J=9.4, 7.1 Hz, 1H), 1.98 (heptupletd, J=6.8, 3.3 Hz, 1H), 1.60(m, 1H), 1.25 (d, J=6.5 Hz, 3H), 0.86 (d, J=7.0 Hz, 3H), 0.81 (s, 9H),0.76 (d, J=6.8 Hz, 3H), 0.70 (d, J=7.0 Hz, 3H), 0.00 (s, 3H), −0.02 (s,3H).

EXAMPLE 10 (4R)-4-isopropyl-5,5-diphenyl-(N)-[(2R, 3S,4S)-3-hydroxy-5-(4-methoxybenzyloxy)-2,4-dimethyl-valeryl]-oxazolidin-2-one

A solution of the PMB ether of Example 9 (162 mg, 0.25 mmol) in 5 mL ofCH₃CN at 23° C. is treated with 0.5 mL of 48% aqu. HF. After stirringfor 24 h, the reaction is quenched with sat. aqu. NaHCO₃ and extractedwith TBME (3 times). The combined organic layers are washed with sat.aqu. NaHCO₃ and sat. aqu. NaCl, dried over MgSO₄, filtered, andconcentrated in vacuo. After purification by FC (SiO₂, heptane/AcOEt3:1), the title compound is obtained as a colorless oil. ¹H-NMR (CDCl₃,300 MHz, 300K) δ 7.45-7.05 (m, 12H), 6.85-6.75 (m, 2H), 5.26 (d, J=3.5Hz, 1H), 4.24 (d, J=11.5 Hz, 1H), 4.15 (d, J=11.5 Hz, 1H), 3.73 (s, 3H),3.70 (qd, J=6.9, 5.4 Hz, 1H), 3.32 (m. 1H), 3.15 (d, J=5.0 Hz, 1H), 3.05(dd, J=9.3, 4.4 Hz, 1H), 2.97 (dd, J=9.3, 5.1 Hz, 1H), 1.90 (heptupletd,J=6.8, 3.5 Hz, 1H), 1.58-1.40 (m, 1H), 1.22 (d, J=6.9 Hz, 3H), 0.80 (d,J=7.0 Hz, 3H), 0.75 (d, J=7.0 Hz, 3H), 0.71 (d, J=6.8 Hz, 3H); HRMS(ESI) m/z 568.2671 ([M+Na]⁺; calcd. for C₃₃H₃₉NO₆: 568.2671).

EXAMPLE 11 (4R)-4-Isopropyl-5,5-diphenyl-(N)-[2-((1S, 3R,6S)-3-(4-methoxyphenyl)-6-methyl-2,4-dioxacyclohex-1-yl)-(2R)-propionyl]-oxazolidin-2-one

To a solution of the alcohol of Example 10 (54 mg, 0.10 mmol) in 1.0 mLof CH₂Cl₂ at 0° C. under an atmosphere of argon, 4 Å molecular sieve (55mg) and DDQ (30 mg, 0,13 mmol, 1.3 eq.) are added sequentially in oneportion. The resulting deep green reaction mixture is stirred at 0° C.for 15 h. A precipitate is formed. After removal of the precipitate byfiltration, concentration in vacuo and PTLC (SiO₂, 10×20 cm plate,heptane/AcOEt 2:1), the title compound is obtained as a colorless oil.¹H-NMR (CDCl₃, 300 MHz, 300K) δ 7.40-7.15 (two m, 8H), 7.22 (d, J=8.7Hz, 2H), 7.07-6.94 (m, 2H), 6.82 (d, J=8.7 Hz, 2H), 5.22 (d, J=3.4 Hz,1H), 4.49 (s, 1H), 4.00 (qd, J=6.9, 3.4 Hz, 1H), 3.85 (dd, J=11.2, 4.6Hz, 1H), 3.75 (s, 3H), 3.13 (t, J=11.2 Hz, 1H), 3.11 (dd, J=9.7, 3.4 Hz,1H), 1.93 (heptupletd, J=6.8, 3.4 Hz, 1H), 1.84-1.70 (m, 1H), 1.19 (d,J=6.9 Hz, 3H), 0.85 (d, J=7.0 Hz, 3H), 0.72 (d, J=6.8 Hz, 3H), 0.53 (d,J=6.8 Hz, 3H).

EXAMPLE 12 (4R)-4-Isopropyl-5,5-diphenyl-(N)-[2-((1S, 3R,6S)-3-(4-methoxyphenyl)-6-methyl-2,4-dioxacyclohex-1-yl)-(2R)-propionyl]-oxazolidin-2-one

A solution of 9.20 g of the diol of Example 6 (21.6 mmol) in 150 mL ofCH₂Cl₂ at ambient temperature is treated sequentially with 2.8 g ofamberlyst 15 and 4.83 g of anisaldehyde dimethyl acetal (24.9 mmol, 1.22eq.). The resulting reaction mixture is stirred for 2.5 h, after whichit is filtered. The filtrate is concentrated in vacuo to give thedesired acetal as a crude residue.

EXAMPLE 13 (3R, 4R)-3-hydroxy-4-((1S, 3R,6S)-3-(4-methoxyphenyl)-6-methyl-2,4-dioxacyclohex-1-yl)-valeric acidtert-butyl ester

To a solution of 825 μL of diisopropylamine (5.84 mmol, 2.9 eq.) in 13mL of a mixture of THF/HMPA (85:15 v/v) at 0° C. under an atmosphere ofargon is added 3.65 mL of BuLi (1.6 M in hexanes, 5.8 mmol, 2.9 eq.).After 15 min at 0° C., the reaction mixture is cooled to −78° C. andtreated with 810 μL of tert-butyl acetate (6.0 mmol, 3.0 eq.). After 30min at −78° C., the reaction mixture is treated by dropwise additionover a period of 10 min with a solution of 529 mg of the aldehyde ofstage 13.2 (2.00 mmol) in 9 mL of THF/HMPA (85:15 v/v). After 15 min at−78° C., the reaction mixture is poured onto 40 mL of sat. aqu. NH₄Cl.The aqu. layer is extracted with TBME (3×40 mL). The combined organiclayers are washed with sat. aqu. NH₄Cl (30 mL), sat. aqu. NaCl (30 mL),dried over MgSO₄, filtered, and concentrated in vacuo. Afterpurification by FC (SiO₂, hexane/AcOEt 4:1), the title compound isobtained as a colorless oil. ¹H-NMR (CDCl₃, 300 MHz, 300K, mixture ofepimers, ratio=3:1) major epimer: δ 7.37 (d, J=8.8 Hz, 2H), 6.85 (d,J=8.8 Hz, 2H), 5.47 (s, 1H), 4.26-4.19 (m, 1H), 4.09 (dd, J=11.3, 4.7Hz, 1H), 3.78 (s, 3H), 3.70 (dd, J=10.0, 2.0 Hz, 1H), 3.51 (t, J=11.1Hz, 1H), 2.51 (dd, J=15.5, 8.2 Hz, 1H), 2.39 (dd, J=15.5, 5.0 Hz, 1H),1.98-2.17 (m, 1H), 1.92-1.78 (m, 1H), 1.44 (s, 9H), 1.04 (d, J=7.1 Hz,3H), 0.74 (d, J=6.7 Hz, 3H); minor epimer: δ 7.34 (d, J=8.9 Hz, 2H),6.86 (d, J=8.9 Hz, 2H), 5.48 (s, 1H), 4.08 (dd, J=11.3, 4.7 Hz, 1H),4.06-3.97 (m, 1H), 3.91 (dd, J=10.1, 1.8 Hz, 1H), 3.79 (s, 3H), 3.52 (t,J=11.1 Hz, 1H), 2.58 (dd, J=16.0, 3.8 Hz, 1H), 2.39 (dd, J=16.0, 8.7 Hz,1H), 1.98?2.17 (m, 1H), 1.92-1.78 (m, 1H), 1.45 (s, 9H), 0.99 (d, J=7.1Hz, 3H), 0.73 (d, J=6.8 Hz, 3H); MS (EI) m/z783 (5, [2 M+Na]⁺), 403(100, [M+Na]⁺), 347 (25, [M+Na—C₂H₈]⁺).

Stage 13.1: To a solution of 12.62 g of the crude acetal of Example 11in 60 mL of THF at 78° C. under an atmosphere of argon is added over aperiod of 30 min 62 mL of a 1 M solution of LiAlH₄ in THF (62 mmol).After 3 h of stirring at −78° C., the reaction mixture is warmed to 0°C. and treated sequentially with 2.4 mL of water, 2.4 mL of 15% aqu.NaOH, and 7.1 mL of water. The resulting precipitate is removed byfiltration and washed with THF (2×10 mL). The filtrate is collected andconcentrated in vacuo to half of its initial volume. A white precipitateis formed during the concentration. Heptane (100 mL) is added and moreof the precipitate is formed. The suspension is evaporated in vacuo tohalf of its initial volume, stirred at 0° C. for 30 min and filtered.The residue is washed with heptane (3×10 mL). The filtrate is collectedand concentrated in vacuo to give the crude desired alcohol as ayellowish oil.

Stage 13.2: A solution of 3.10 g of oxalyl chloride (24 mmol) in 40 mLof CH₂Cl₂ at −78° C. under an atmosphere of argon is treatedsequentially by dropwise addition of a solution of 4.22 g of DMSO (54mmol) in 16 mL of CH₂Cl₂ and a solution of the crude alcohol of stage13.1 (6.20 g) in 30 mL of CH₂Cl₂. The resulting reaction mixture isstirred at −78° C. for 30 min. The reaction mixture is then treated bydropwise addition of 18.5 mL of diisoproylethylamine (108 mmol) and isstirred at −78° C. for 1 h before being warmed to 0° C. Water (70 mL) isadded and the aqu. layer is extracted with CH₂Cl₂ (2×40 mL). Thecombined organic layers are washed with sat. aqu. NaCl (2×50 mL), driedover MgSO₄, filtered, and concentrated in vacuo. After purification byFC (SiO₂, heptane/AcOEt 3:1), the desired aldehyde is obtained as acolorless oil. ¹H-NMR (CDCl₃, 300 MHz, 300K) δ 9.76 (s, 1H), 7.33 (d,J=8.8 Hz, 2H), 6.86 (d, J=8.8 Hz, 2H), 5.48 (s, 1H), 4.15 (dd, J=11.3,4.7 Hz, 1H), 4.07 (dd, J=10.1, 2.50 Hz, 1H), 3.79 (s, 3H), 3.58 (dd,J=11.3 Hz, 1H), 2.58 (qd, J=7.1, 2.5 Hz, 1H), 2.10 (ddqd, J=11.3, 10.1,6.7, 4.7, Hz, 1H), 1.24 (d, J=7.1 Hz, 3H), 0.81 (d, J=6.7 Hz, 3H).

EXAMPLE 14

To a stirred solution of LDA (0.71 mmol, prepared from 0.77 mmol ofdiisopropylamine and 0.71 mmol of Buli 1.6 M in hexanes at 0° C.) in THF(0.30 mL) at −50° C. under an atmosphere of argon is added a solution ofthe product from Example 13 (118 mg, 0.31 mmol) in THF (0.30 mL). Thereaction mixture is allowed to warm to −10° C. and stirred at thattemperature for 10 min. The reaction mixture is then cooled to −50° C.and stirred at that temperature for 30 min. A solution of the productfrom stage 8.4 (244 mg, 0.42 mmol) in a mixture of THF (0.10 mL) andHMPA (0.10 mL) is added. The reaction mixture is stirred for 2 h at −50°C. before being diluted with TBME (2 mL) and poured into an aqu. sat.solution of NH₄Cl (2 mL). The reaction mixture is then partitionedbetween NaHCO₃ (2×5 mL) and TBME (2×5 mL). The combined organic extractsare washed with NaCl (5 mL), dried (MgSO₄) and concentrated in vacuo.Filtration over SiO₂ (5% EtOAc/Hexanes) provides the product as acolourless oil; MS (EI) m/z801 (100, [M+Na]⁺).

EXAMPLE 15

To a stirred solution of the crude product of stage 15.3 (350 mg, 0.39mmol) in THF (10 mL) at −78° C. is added LiAlH₄ (4.0 mL of a 1M/THFsolution, 4.00 mmol) and allowed to gradually warm to −10° C. over 1.5h. The reaction is then quenched by the addition of MeOH (2 mL) andpartitioned between potassium sodium tartrate (15 mL) and TBME (3×50mL). The combined organic extracts are dried (MgSO₄) and concentrated invacuo. Flash chromatography (95% EtOAc/hexane) gives the desiredcompound as a colourless solid; IR (KBr): v_(max) 2959 s, 2930 s, 2857s, 1472 m, 1462 m, 1250 s, 1113 m, 1083 s, 1062 s, 1038 m, 1019 s, 1005w, 856 w, 835 s, 774 s; ¹H-NMR (CDCl₃, 500 MHz, 298K) δ 7.85 (dt, J=9.0,2.0 Hz, 2H), 6.88 (dt, J=9.0, 2.0 Hz, 2H), 5.39 (s, 1H), 5.07 (d, J=10.0Hz, 1H), 4.10 (dd, J=11.0, 4.5 Hz, 1H), 3.80 (s, 3H), 3.63 (dd, J=5.0,2.0 Hz, 1H), 3.62 (dd, J=10.0, 5.0 Hz, 1H), 3.52 (dd, J=10.0, 2.0 Hz,1H), 3.48 (t, J=11.5 Hz, 1H), 3.43 (t, J=5.5 Hz, 1H), 3.36 (dd, J=10.0,8.0 Hz, 1H), 2.51 (m, 1H), 2.34 (t, J=12.0 Hz, 1H), 2.06 (m, 1H), 1.99(m, 1H), 1.88 (td, J=7.0, 1.5 Hz, 1H), 1.80 (m, 1H), 1.71 (br d, J=11Hz, 1H), 1.58 (s, 3H), 1.02 (d, J=7.0 Hz, 3H), 0.91 (d, J=7 Hz, 3H),0.91 (s, 9H), 0.90 (s, 9H), 0.89 (d, J=7 Hz, 3H), 0.889 (s, 9H), 0.76(d, J=7.0 Hz, 3H), 0.75 (d, J=6.50 Hz, 3H), 0.05 (s, 3H), 0.04 (s, 3H),0.02 (s, 9H), 0.01 (s, 3H); ¹³C-NMR (CDCl₃, 125 MHz, 300K) δ 131.8,131.7, 127.5, 114.5, 113.6, 101.2, 83.6, 78.6, 77.7, 73.5, 65.5, 55.4,41.5, 38.3, 37.5, 35.4, 34.0, 31.0, 26.1, 26.0, 25.8, 23.3, 18.6, 18.5,16.8, 13.8, 12.8, 12.3, 11.0, 5.9, −3.3, −3.4, −3.5, −3.6, −3.8, −5.1;MS (EI) m/z: 829 (7, [M+Na]⁺), 826 (17, [2M+Ca]²⁺), 377 (90), 313 (100).

Stage 15.1: To a stirred solution of the crude product of Example 14(400 mg, 0.51 mmol) in CH₂Cl₂ (10 mL) at −78° C. Et₃N (714 μL, 5.13mmol) is added, followed by addition of TBDMSOTf (586 μL, 2.55 mmol).The reaction mixture is allowed to warm to RT and stirred for 4 h. Thereaction mixture is then partitioned between NaHCO₃ (20 mL) and CH₂Cl₂(3×50 mL). The combined organic extracts are dried (MgSO₄) andconcentrated in vacuo. Filtration over SiO₂ (5% EtOAc/Hexanes) gives thecrude product as a colourless oil; MS (EI) m/z 915 (100, [M+Na]⁺).

Stage 15.2: To a stirred solution of the crude product of stage 15.1(561 mg, 0.63 mmol) in THF (15 mL) at −78° C. is added LiAlH₄ (6.30 mLof a 1M/THF solution, 6.30 mmol). The reaction mixture is allowed togradually warm to −15° C. over 1 h. The reaction mixture is thenquenched by the careful addition of a aqu. solution of potassium sodiumtartrate (30 mL) and stirred vigorously at RT. After 30 min, the layersare separated and the aqu. layer is extracted with TBME (3×100 mL). Thecombined organics are dried (Na₂SO₄) and concentrated in vacuo.Filtration over SiO₂ (5-30% EtOAc/Hexanes) provides the desired alcoholas a colourless oil; MS (EI) m/z 923 (100, [M+Na]⁺).

Stage 15.3: To a stirred solution of the crude product of stage 15.2(400 mg, 0.49 mmol) in CH₂Cl₂ (10 mL) at RT is added Et₃N (338 μL, 2.43mmol) and methanesulfonylchloride (58 μL, 0.74 mmol). After 20 h themixture is partitioned between NaHCO₃ (15 mL) and CH₂Cl₂ (3×20 mL). Thecombined organic extracts are dried (Na₂SO₄) and concentrated in vacuo.Filtration over SiO₂ (10-20% EtOAc/Hexanes) gives the crude product as acolourless oil; MS (EI) m/z 891 (100, [M+Na]⁺).

1. A process for preparing a substituted alkene of formula I

wherein R₁, R₂ and R₃ are independently of each other a protecting groupfor a hydroxy group or hydrogen and R₄ is phenyl which is unsubstitutedor mono- or disubstituted by alkoxy, in which process a carboxylic esterof the formula III

wherein R₁, R₂ and R₃ are all protecting groups for a hydroxy groupwhich protecting groups can be identical or different, R₆ is alkyl orarylalkyl, and R₄ has the meaning as defined for the compound of formulaI, is first reduced, to obtain alcohol of the formula IV

wherein R₁, R₂, R₃ and R₄ have the meanings as defined for the compoundof formula III, is further reacted with a compound of formula VR₅SO₂Hal  (V) wherein R₅ is alkyl or aryl which is unsubstituted orsubstituted by alkyl, and Hal represent halogen, and the obtainedsulfonate of formula II

wherein R₁, R₂, R₃ and R₄ have the meanings as defined for thecarboxylic ester of formula III and R₅ is alkyl or aryl which isunsubstituted or substituted by alkyl, is further reduced, and, ifdesired, one, two or all protecting groups R₁, R₂ and R₃ are detached bymethods known in the art to obtain a compound of formula I.
 2. A processfor preparing a carboxylic ester of formula II

wherein R₁ and R₂ are protecting groups for a hydroxy group whichprotecting groups can be identical or different or hydrogen, R₃ ishydrogen, R₄ is phenyl which is unsubstituted or mono- or disubstitutedby alkoxy, and R₆ is alkyl or arylalkyl, in which process an allylhalide of the formula VI

wherein R₁ and R₂ have the meanings as defined for a carboxylic ester offormula III and X is halogen, is reacted with a carboxylic ester offormula VII

wherein R₃, R₄ and R₆ have the meanings as defined for a carboxylicester of formula III in the presence of a base, and afterwards, ifdesired, one or all protecting groups R₁ and R₂ are split off to obtaina compound of formula III.
 3. A process according to claim 1 wherein R₁and R₂ are identical and R₁, R₂ and R₃ are silyl protecting groups.
 4. Asulfonate of formula II

wherein R₁, R₂ and R₃ are all protecting groups for a hydroxy groupwhich protecting groups can be identical or different, R₄ is phenylwhich is unsubstituted or mono- or disubstituted by alkoxy, and R₅ isalkyl or aryl which is unsubstituted or substituted by alkyl.
 5. Asulfonate of formula II according to claim 4 wherein R₁ and R₂ areidentical, R₁, R₂ and R₃ are benzyl or silyl protecting groups, R₄ isphenyl which is unsubstituted or mono- or disubstituted by alkoxy, andR₅ is lower alkyl or phenyl which is substituted by lower alkyl.
 6. Asulfonate of formula II according to claim 4 wherein R₁ and R₂ and R₃are tert-butyl dimethylsilyl, R₄ is phenyl which is unsubstituted ormonosubstituted by lower alkoxy and R₅ is lower alkyl or phenyl which ismonosubstituted by lower alkyl.
 7. A carboxylic ester of formula III

wherein R₁ and R₂ are protecting groups for a hydroxy group whichprotecting groups can be identical or different, R₃ is a protectinggroup for a hydroxy group or hydrogen, R₄ is phenyl which isunsubstituted or mono- or disubstituted by alkoxy, and R₆ is alkyl orarylalkyl.
 8. A carboxylic ester of formula III according to claim 7wherein R₁ and R₂ are identical, R₁, R₂ and R₃ are silyl protectinggroups and R₆ is lower alkyl.
 9. An alcohol of formula IV

wherein R₁, R₂ and R₃ are all protecting groups for a hydroxy groupwhich protecting groups can be identical or different and R₄ is phenylwhich is unsubstituted or mono- or disubstituted by alkoxy.